Healthy human brains have a daily heatwave

around 18 mm below the dura), in patients with moderate-to-severe brain trauma. Data collected in the context of Targeted Temperature Management were excluded. Rhythmicity analyses were performed on datasets where at least 36 h of continuous data were obtained, using strict criteria and a multiplexed algorithm approach [1]. A generalized linear mixed model was applied to determine whether there was any relationship between T Br features and patient outcome. Patients with a daily rhythm in brain temperature (colored circles) had a greater chance of survival in intensive care ( P = 0.016; n = 98).

decreased with age, suggesting a reduced variability in older patients. Next, we recruited 40 healthy adults aged 20-40 years for brain imaging. Participants were scanned in the morning, afternoon, and late evening of a single day, immediately after one week of actigraphy. This allowed us to control for differences in chronotype-how an individual's body clock aligns with the day-night cycle-which could have masked a true daily variation in T Br across the group. We used a validated MRS technique to measure T Br in several locations within the cerebrum and deeper areas including the thalamus and hypothalamus-a key brain structure involved in biological timing and thermoregulation. In healthy adults, mean T Br exceeded oral temperature and varied spatially by 2.4°C with highest temperatures in the thalamus, the most central brain region measured. Across the cohort and all time points, T Br ranged from 36.1 to 40.9°C, whilst oral temperature varied less (34.6 to 37.0°C). Notably, T Br increased with age, especially in deep brain regions with a 0.6°C increase between ages 20 and 40. T Br varied by time of day, being lowest at night in both sexes, but on average it was 0.4°C higher in post-ovulation females relative to pre-ovulation females and males, and this difference was exaggerated 2-fold in deep brain regions. The time of day variation was also greatest in deep brain regions with nearly a 1°C drop by midnight.
We used our MRS data to model T Br over a complete day-night cycle to produce HEATWAVE-the first 4D map of normal human T Br . HEATWAVE has yielded results that are physiologically intuitive, yet neurologically surprising. Human T Br is clearly higher and varies more than previously assumed. Sex differences appear to be driven by menstrual cycle phase, whilst time of day variation reflects established daily rhythms in temperature measured in other parts of the body. Since cerebral blood flow is key to brain heat transfer, a nightly fall in T Br temporally aligns with increased cerebral blood flow during sleep [1] and temperature gradients across the brain agree with predictions from cerebrovascular anatomy and thermodynamics. Age-related changes in cerebrovascular function might underlie progressive impairment of brain cooling-but this remains to be formally tested. Conceptually, an age-related T Br increase should be partially offset by advancing brain atrophy and the loss of heat-generating tissue, leading to nonlinearity in later years. An important question emerging from our data is whether the daily T Br range would decrease in the aged brain, mirroring a reduced amplitude in temperature rhythms observed in other parts of the body [1]. In this regard, the wider physiological state of an individual (in particular hydration and acclimatization) would be expected to influence thermoregulatory capacity and thus T Br extremes over a 24-hour period. The marked spatial distribution of T Br presents the conceptual challenge of how neural circuits spanning such a temperature gradient could deal with, or indeed exploit, it. More perplexing are the larger temperature gradients that might exist within the longest cells in the body. The selective vulnerability of certain motor neuronal subtypes in some of the most devastating neurological disorders may be compounded or partially explained by spatiotemporal temperature variation.
Spatiotemporal variation in T Br is likely to have a complex, and perhaps reciprocal relationship with sleep. The mechanistic basis of sleep and its purpose are uncertain, but our data are consistent with a thermal hypothesis for sleep function and evolution, wherein T Br decline is permissive for entry into non-rapid eye movement sleep, whilst rapid eye movement sleep serves to keep T Br above a vital threshold [6]. Sleep disturbance in hot weather might thus represent a failure of T Br to fall at the required rate, or reach the required minima for some sleep stages. Intriguingly, HEATWAVE predicts a greater daily excursion of temperature in deep brain regions in males; future studies should extend measurement into other parts of the brainstem that play a role in sleep. T Br dynamics illuminated by HEATWAVE ultimately demand a reappraisal of how daily neuronal activity is regulated and, in effect, how the brain works. In proposing such a paradigm shift, parallels can be drawn with the derailment of Galenic doctrine which asserted that humans had an intracranial rete mirabile. For much of the sixteenth and seventeenth centuries this intricate brain-cooling vasculature was falsely depicted as a feature of human anatomy based on its demonstration in other species [7]. This costly mistake, perpetuated by Galen's acolytes, exemplifies the dangers of reliance on established authority over direct observation. Challenging embedded beliefs, our findings can stimulate further research into the mechanistic underpinnings of T Br in health and disease.
Having established a baseline for normal human T Br and its spatiotemporal variation-what does this mean for patients? Evidently, our retrospective dataset contained injured brains that were above, below, or within the normal range of T Br , but not necessarily all of the time. Looking again at these data we tested which features of T Br were related to outcome. Ageing by 10 years increased the odds of death 11-fold and a warmer mean T Br was associated with survival, but neither temperature maxima, minima, nor range predicted mortality. Most strikingly, however, lack of a daily T Br rhythm increased the odds of death in intensive care 21-fold [1]. In real terms, of 98 patients in our outcome analysis (Fig.1), 21 died and only one of these had a daily rhythm in T Br . By contrast, of the 77 who survived, 24 had a daily rhythm in T Br . Thus, it seems that T Br variation, rather than absolute T Br , better distinguishes brain function and dysfunction. The 'take home' is not that the lack of a daily T Br rhythm reliably predicts death, but that the presence of this rhythm alone is a positive sign that should be factored into decision making. Whilst larger prospective studies are needed to validate these results, our findings extend the prognostic power of T Br and raise questions about how patient temperature is currently managed and interpreted-not least that the T Br recorded from a patient depends on factors unrelated to their brain injury.
HEATWAVE thus provides a valuable reference dataset for future studies in different age groups and patient cohorts. For example, T Br variability might predict and influence the manifestation of chronic brain disorders. Indeed, we can readily envisage clinical trials to assess the utility of T Br rhythm disruption as an early biomarker for neurodegenerative disease. Achieving this at scale will require the development of cost-effective, practical, and non-invasive technologies to capture longitudinal variations in temperature across the brain.
Abnormal body temperature rhythms feature early in neurodegenerative disorders and are considered a manifestation of disrupted sleep and circadian cycles. If T Br rhythms are similarly affected, it will be critical to establish how normal T Br variation interacts with the daily neural molecular clockwork before inferring a role for T Br disruption in disease.
To this end, HEATWAVE is transforming how we explore neural circadian oscillations in the lab, and how key molecular components of these biological clocks operate within the rhythmic biophysical environment of the cell. Whilst these new data raise more questions than they answer, the human brain can no longer be viewed as an isothermal machine. A multicentre, retrospective analysis was conducted using all available T Br data from the CENTER-TBI High Resolution ICU Sub-Study [1]. These data were collected at a minimum of 1-min intervals from a single location in frontal white matter (around 18 mm below the dura), in patients with moderate to severe brain trauma. Data collected in the context of Targeted Temperature Management were excluded. Rhythmicity analyses were performed on datasets where at least 36 h of continuous data were obtained, using strict criteria and a multiplexed algorithm approach [1]. A generalized linear mixed model was applied to determine whether there was any relationship between T Br features and patient outcome.
Patients with a daily rhythm in brain temperature (coloured circles) had a greater chance of survival in intensive care (P=0.016; n=98).